INVESTIGATIONS OF THE PENICILIN - -CYCLODEXTRINE COMPLEX BY
SEMIEMPIRICAL METHODS
C. I. Morari1, C. Ionescu2
1
National Institute for Research and Development of Isotopic and
Molecular Technologies, R-3400 Cluj-Napoca, P.O. 5, Box 700,
Romania
2
I.Hatieganu University of Medicine and Pharmacy, Faculty of
Pharmacy, Dept.of Biochemistry and Clinical laboratory, R-3400,
Cluj-Napoca, Romania
Abstract
Two simulation of the  - CD penicilin docking complex are presented. The
calculations were performed at semiempirical level (PM3 and AM1). The
values of binding energies of the complexes and the MOPAC charge analysis
are discussed for both models.
Introduction
Penicillin V is a narrow spectrum, b-lactamase-labile antibiotic. Still, being acid-stable
(unlike penicillin G, for instance) it can be orally given, consequently providing a
better compliance of the patients. The aim of the present study is to design a new orally
form of administration for penicillin V with enhanced stability to b-lactamases; this is
consequent with the fact that resistance of bacteria to b- lactam antibiotics may be
associated with enzymes termed b-lactamases. Susceptible penicillins are converted to
the corresponding penicilloic acid which is inactive. On the other hand, alterations in
the molecule (by substitution) can produce penicillins with changes in microbiological
and/or pharmacological properties. Our idea is to complex the penicillin with cyclodextrin, a modern and more and more used vehicle for drugs from different
classes. It has been demonstrated that cyclodextrins may improve absorption, stability
and bioavailability.
Obtaining a good simulation of the processes involving the interaction between a drug
molecule and a cyclodextrin represents a difficult task. Among the difficulties
involved by these calculations the size of the system and the presence of hydrogen
bonds are to be mentioned. In order to overcome these problems and still to keep a
good level of accuracy, we performed a study of the docking process of the peniciline
into beta - CD by using the semiempirical PM3 and AM1 methods. Our aim was to
give a numerical simulation of the process.
The steps of the simulations were: (i) the geometry for the peniciline was optimized;
(ii)the complex -CD - peniciline was set us using the MOLDEN package; (iii) the
equilibrium geometry and the binding energy were computed. All the calculations were
performed using the GAMESS package. The binding energies and the Mopac charges
are reported. Altogether, these results allow us to draw valuable conclusions about the
nature and the strength of the forces into the complex.
Computational method
The molecular modeling of the host - guest interaction by semiempirical methods was
performed in three steps:
(i) The Z matrices for the equilibrium structures of CD and penicilin were builded up.
The structure  - CD was taken from Cambridge Structural Database [1]. We
considered that this structure changes very little during the complexation process. As a
consequence of this approach, no further theoretical optimization were performed on
these structures. The initial structure of penicilin was builded up using the Hyperchem
5 program. This initial structure was optimized at ab initio level by using the PM3
approach; for all calculations the GAMESS package was used [3]. The resulting
structure of penicilin is depicted in Figure 1.
Figure 1: Molecular structure of penicilin
(ii) The optimization strategy consisted in keeping frozen all the internal coordinates of
the CD, while the relative orientation CD - pencicilin and the internal geometry of the
penicilin molecule were optimized. The semiempirical methods PM3 and AM1 were
used to this end [4].
Results
Table 1 summarize the results of Mopac charge analysis [4] of the complex CD penicilin for different computational models. The binding energy for the complex are
also given in eV. The small value of the Mopac charge aquired by penicillin shows that
the nature of the binding interaction is probably a Van der Waals – like interaction.
The binding energy is sufficiently large to enshure the stability of the complex at the
room temperature (kB T =0.026 eV at room temperature).
Table 1: Binding energy of the complex and the sum of the total Mopac charges over the atoms
of penicilin for different computational models (PM3 and AM1)
Computational model Binding energy [eV] Mopac charge of penicilin
AM1
0.20
-0.0018
PM3
0.46
-0.006
The resulting equilibrium PM3 and AM1 geometries are given in Figures 3 and 4.
It can be seen that in the complex the penicilin lies close to the symmetry axis of the
CD molecule, for both computational models. A possible explanation of this behavior
is that the long range forces are dominant into the complex. This situation leads to a
complex that follows the symmetry of the CD molecule since at large distance the
binding forces appear to be averaged.
Figure 3: Equilibrium geometries, PM3 level for -CD + penicilin complex. Left: lateral view.
Right: top view.
Figure 4: Equilibrium geometries, AM1 level for -CD + penicilin complex. Left: lateral view.
Right: top view.
Conclusion
A theoretical investigation of the stability of the -CD + penicilin complex was
performed. Semiempirical PM3 and AM1 methods were employed to investigate the
nature of the interaction inside the complex. The binding energies are 10-20 times
larger than the thermal energy (kB T =0.026 eV at room temperature). These values
suggests that the complex is stable at room temperature. The Mopac population
analysis shows that the charge transfer plays a negligible role into the docking process.
Using the geometry of the system we propose as main contribution to the binding
forces of the system the long range components of the intermolecular potential.
References
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October 1999, Cambridge Crystallographic Data Centre, University Chemical Laboratory,
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N.Matsunaga, K.A.Nguyen, S.J.Su, T.L.Windus, M.Dupuis, J.A.Montgomery,
J. Comput. Chem., 14 1347-1363 (1993)
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